Methods of preparing secondary carbinamine compounds with boronic acids

ABSTRACT

The present application relates to novel methods for the preparation of secondary carbinamine compounds, particularly the preparation of secondary carbinamine compounds of the formula Ia, formula Ib or formula IV from aldehydes of the formula II and boronic acids of the formula III or formula V, in the presence of ammonia or an ammonia equivalent of the formula NH 4+X− .

FIELD OF THE APPLICATION

The present application relates to novel methods for the preparation ofsecondary carbinamine compounds, particularly the preparation ofsecondary carbinamine compounds from aldehydes and boronic acids in thepresence of ammonia.

BACKGROUND OF THE APPLICATION

Amines are one of the most common classes of organic molecules. Theyplay important roles in a variety of areas, ranging from thepharmaceutical industry to plastics manufacturing.

Current methods for the synthesis of amines generally rely on multi-stepprocesses that convert a variety of amine precursors to the amino (NH₂)functional group itself. To date, with the singular exception of twoexisting methodologies, there has been no general method for the directsynthesis of amines from ammonia. Since ammonia is an inexpensive bulkcommodity chemical that is manufactured on a multi-ton scale annually,any process that allows for the direct use of ammonia for theintroduction of the amino group is therefore highly desirable.

Research into the addition of allyl organometallics to carbonylcompounds and their derivatives continues to proceed unabated—aconsequence of the fact that the resulting homoallylic products haveproven to be valuable synthons [Denmark, S. E. and Almstead, N. G.,Modern Carbonyl Chemistry, ed. Otera, J. Wiley-VCH, Weinheim, 2000, ch.10; Yamamoto, Y. and Asao, N., Chem. Rev., 1993, 93, 2207; and Roush, W.R., Comprehensive Organic Synthesis, ed. Trost, B. M., Fleming, I. andHeathcock, C. H., Pergamon, Oxford, 2nd edn., 1991, vol. 2, pp 1-53].The majority of the research, however, has focused on the addition ofallylboronic esters to aldehydes. For example, the reaction of

has previously been described by Kobayashi et al. [M. Sugiura, K. Hiranoand S. Kobayashi, J. Am. Chem. Soc., 2004, 126, 7182-7183; S. Kobayashi,K. Hirano and M. Sugiura, J. Chem. Commun., 2005, 104-105].

A methodology for the diastereoselective addition of allyl- andcrotyl-boronic acids to ketones in the presence of methanolic ammonia toproduce tertiary homoallylic amines was recently reported [Dhudshia, B.,Tiburcio, J. and Thadani, A. N. Chem. Commun. 2005, 5551-5553].

SUMMARY OF THE APPLICATION

Methods for the direct addition of a variety of nucleophiles toaldehydes in the presence of ammonia have been shown to afford thecorresponding secondary carbinamine compounds in moderate to excellentyields under mild reaction conditions. The methods have been shown to besimple and efficient for the incorporation of ammonia into thecarbinamine end-products.

Accordingly, the present application includes a method of preparing asecondary amine of the formula Ia and/or Ib:

whereinR¹ is selected from C₁₋₂₀alkyl, C₁₋₂₀alkoxy, C₂₋₂₀alkenyl, C₂₋₂₀alkynyl,C₃₋₂₀cycloalkyl, C₃₋₂₀cycloalkoxy, aryl, aryloxy, heteroaryl andheteroaryloxy, all of which are optionally substituted and one or moreof the carbons in C₁₋₂₀alkyl, C₁₋₂₀alkoxy, C₂₋₂₀alkenyl, C₂₋₂₀alknyl,C₃₋₂₀cycloalkyl or C₃₋₂₀cycloalkoxy is optionally replaced with aheteromoiety selected from O, S, N, NR⁷ and NR⁷R⁸;R² to R⁶ are independently selected from H, C₁₋₂₀alkyl, C₁₋₂₀alkoxy,C₂₋₂₀alkenyl, C₂₋₂₀alkynyl, C₃₋₂₀cycloalkyl, C₃₋₂₀cycloalkoxy, aryl,aryloxy, heteroaryl and heteroaryloxy, the latter 9 groups beingoptionally substituted and one or more of the carbons in C₁₋₂₀alkyl,C₁₋₂₀alkoxy, C₂₋₂₀alkenyl, C₂₋₂₀alkynyl, C₃₋₂₀cycloalkyl orC₃₋₂₀cycloalkoxy is optionally replaced with a heteromoiety selectedfrom O, S, N, NR⁷ and NR⁷R⁸;R⁷ and R⁸ are independently selected from H, C₁₋₂₀alkyl,C₃₋₂₀cycloalkyl, aryl and heteroaryl, the latter 4 groups beingoptionally substituted; comprising reacting a compound of formula II:

wherein R¹ is as defined for the compounds of formulae Ia and Ib, with acompound of formula III:

wherein R²-R⁶ are as defined for the compounds of formulae Ia and Ib, inthe presence of ammonia NH₃ or an ammonia equivalent of the formula NH₄⁺X⁻, wherein X is an anionic counterion, and optionally isolating theamine of the formula Ia and/or Ib.

In another aspect, the present application relates to a method ofpreparing an amine of the formula IV:

whereinR¹ is selected from C₁₋₂₀alkyl, C₁₋₂₀alkoxy, C₂₋₂₀alkenyl, C₂₋₂₀alkynyl,C₃₋₂₀cycloalkyl, C₃₋₂₀cycloalkoxy, aryl, aryloxy, heteroaryl andheteroaryloxy, all of which are optionally substituted and one or moreof the carbons in C₁₋₂₀alkyl, C₁₋₂₀alkoxy, C₂₋₂₀alkenyl, C₂₋₂₀alkynyl,C₃₋₂₀cycloalkyl or C₃₋₂₀cycloalkoxy is optionally replaced with aheteromoiety selected from O, S, N, NR⁷ and NR⁷R⁸;R¹⁰ is aryl or heteroaryl, both of which are optionally substituted; andR⁷ and R⁸ are independently selected from H, C₁₋₂₀alkyl, C₂₋₂₀alkynyl,C₃₋₂₀cycloalkyl, aryl and heteroaryl, the latter 4 groups beingoptionally substituted; comprising reacting a compound of the formulaII:

wherein R¹ is as defined for the compounds of formula IV, with acompound of the formula V:

wherein R¹⁰ is as defined for the compound of formula IV, in thepresence of ammonia NH₃ or an ammonia equivalent of the formula NH₄ ⁺X⁻,wherein X is an anionic counterion, and optionally isolating the amineof the formula IV.

It is an embodiment of the present application that the method ofpreparing the compounds of the formulae Ia, Ib and IV is performed inthe presence of a catalyst, such as a transition metal catalyst. In afurther embodiment, the catalyst comprises a chiral ligand and its useresults in the preparation of enantiomerically enriched compounds offormulae Ia, Ib and IV.

Other features and advantages of the present application will becomeapparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples while indicating preferred embodiments of the application aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the application will becomeapparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE APPLICATION Definitions

The term “C_(1-n)alkyl” as used herein means straight and/or branchedchain alkyl groups containing from one to n carbon atoms and includes,depending on the identity of n, methyl, ethyl, propyl, isopropyl,t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,hexadecyl, octadecyl, icosyl and the like and wherein n is an integerrepresenting the maximum number of carbon atoms in the group.

The term “C_(3-n)cycloalkyl” as used herein means saturated cyclic orpolycyclic alkyl groups containing from three to n carbon atoms andincludes, depending on the identity of n, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl, cyclododecyl, cyclohexadecyl, cyclooctadecyl,cycloicosyl, adamantyl and the like, and wherein n is an integerrepresenting the maximum number of carbon atoms in the group.

The term “C_(1-n)alkoxy” as used herein means straight and/or branchedchain alkoxy groups containing from one to n carbon atoms and includes,depending on the identity of n, methoxy, ethoxy, propoxy, isopropoxy,t-butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy,dodecoxy, hexadecoxy, octadecoxy, icosoxy and the like, and wherein n isan integer representing the maximum number of carbon atoms in the group.

The term “C_(3-n)cycloalkoxy” as used herein means saturated cyclic orpolycyclic alkoxy groups containing from three to n carbon atoms andincludes, depending on the identity of n, cyclopropoxy, cyclobutoxy,cyclopentoxy, cyclohexoxy, cycloheptoxy, cyclooctoxy, cyclononoxy,cyclodecoxy, cycloundecoxy, cyclododecoxy, cyclohexadecoxy,cyclooctadecoxy, cycloicosoxy and the like, and wherein n is an integerrepresenting the maximum number of carbon atoms in the group.

The term “C_(2-n)alkenyl” as used herein means straight and/or branchedchain alkenyl groups containing from two to n carbon atoms and one tosix double bonds and includes, depending on the identity of n, vinyl,allyl, 1-butenyl, 2-hexenyl and the like, and wherein n is an integerrepresenting the maximum number of carbon atoms in the group.

The term “C_(2-n)alkynyl” as used herein means straight or branchedchain alkynyl groups containing from 2 to n carbon atoms and one to sixtriple bonds and includes, depending on the identity of n, propargyl,1-butynyl, 2-hexynyl and the like, and wherein n is an integerrepresenting the maximum number of carbon atoms in the group.

The term “halo-substituted C_(1-n)alkyl” as used herein means straightor branched chain, saturated alkyl radicals containing from one to ncarbon atoms in which one or all of the hydrogen atoms have beenreplaced with a halogen, in particular fluorine, and includes (dependingon the identity of “n”) trifluoromethyl, pentafluoroethyl, fluoromethyland the like, where the variable n is an integer representing thelargest number of carbon atoms in the alkyl radical.

The term “halo-substituted C_(1-n)alkoxy” as used herein means straightor branched chain, saturated alkoxy radicals containing from one to ncarbon atoms in which one or all of the hydrogen atoms have beenreplaced with a halogen, in particular fluorine, and includes (dependingon the identity of “n”) trifluoromethoxy, pentafluoroethoxy,fluoromethoxy and the like, where the variable n is an integerrepresenting the largest number of carbon atoms in the alkoxy radical.

The term “aryl” as used herein means a monocyclic or polycycliccarbocyclic ring system containing one or two aromatic rings and from 6to 14 carbon atoms and includes phenyl, naphthyl, anthraceneyl,1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl,indenyl and the like.

The term “heteroaryl” as used herein means mono- or polycyclicheteroaromatic radicals containing from 5 to 14 atoms, of which 1 to 4atoms are a heteroatom selected from nitrogen, oxygen and sulfur andincludes furanyl, thienyl, pyrrolo, pyridyl, indolo, benzofuranyl andthe like.

The term “halo” as used herein means halogen and includes chloro,fluoro, bromo and iodo.

The term “one or more” as used herein means that from one to the maximumallowable substitutions are allowed.

The term “optionally substituted” means unsubstituted or substituted.When a group is substituted it may be substituted one or more times, oneto five times, one to three times, one to two times or one time.

The term “ammonia equivalent” as used here refers to a compound thatreacts in situ to produce an equivalent of “NH₃” or ammonia.

The term “enantiomerically enriched” as used herein means a mixture ofenantiomeric compounds that contains an excess of one enantiomer overthe other(s).

The present application includes combinations of groups and substituentsthat are permitted and would provide a stable chemical entity accordingto standard chemical knowledge as would be known to those skilled in theart.

Methods of the Application

A new method for the preparation of secondary carbinamine compounds fromthe diastereoselective allylation and crotylation of aldehydes in thepresence of ammonia has been developed. The method has been shown toprovide the homoallylic amines in high yields through simple acid-baseextraction.

Accordingly, the present application relates to a method of preparing asecondary amine of the formula Ia and/or Ib:

whereinR¹ is selected from C₁₋₂₀alkyl, C₁₋₂₀alkoxy, C₂₋₂₀alkenyl, C₂₋₂₀alkynyl,C₃₋₂₀cycloalkyl, C₃₋₂₀cycloalkoxy, aryl, aryloxy, heteroaryl andheteroaryloxy, all of which are optionally substituted and one or moreof the carbons in C₁₋₂₀alkyl, C₁₋₂₀alkoxy, C₂₋₂₀alkenyl, C₂₋₂₀alknyl,C₃₋₂₀cycloalkyl or C₃₋₂₀cycloalkoxy is optionally replaced with aheteromoiety selected from O, S, N, NR⁷ and NR⁷R⁸;R² to R⁶ are independently selected from H, C₁₋₂₀alkyl, C₁₋₂₀alkoxy,C₂₋₂₀alkenyl, C₂₋₂₀alkynyl, C₃₋₂₀cycloalkyl, C₃₋₂₀cycloalkoxy, aryl,aryloxy, heteroaryl and heteroaryloxy, the latter 9 groups beingoptionally substituted and one or more of the carbons in C₁₋₂₀alkyl,C₁₋₂₀alkoxy, C₂₋₂₀alkenyl, C₂₋₂₀alkynyl, C₃₋₂₀cycloalkyl orC₃₋₂₀cycloalkoxy is optionally replaced with a heteromoiety selectedfrom O, S, N, NR⁷ and NR⁷R⁸;R⁷ and R⁸ are independently selected from H, C₁₋₂₀alkyl,C₃₋₂₀cycloalkyl, aryl and heteroaryl, the latter 4 groups beingoptionally substituted;comprising reacting a compound of formula II:

wherein R¹ is as defined for the compounds of formula Ia and Ib, with acompound of formula III:

wherein R²-R⁶ are as defined for the compounds of formulae Ia and Ib, inthe presence of ammonia NH₃ or an ammonia equivalent of the formula NH₄⁺X⁻, wherein X is an anionic counterion, and optionally isolating theamine of the formulae Ia and/or Ib.

It is an embodiment of the application that the compounds of formulaeIa, Ib and II include those in which R¹ is selected from C₁₋₁₀alkyl,C₃₋₈cycloalkyl, aryl, and heteroaryl, all of which are optionallysubstituted. In another embodiment of the application, one or more ofthe carbons in C₁₋₁₀alkyl or C₃₋₈cycloalkyl is optionally replaced witha heteromoiety selected from O, S, N, NR⁷ and NR⁷R⁸, in which R⁷ and R⁸are independently selected from H and C₁₋₆alkyl. Suitably, one or moreof the carbons in C₁₋₁₈alkyl or C₃₋₈cycloalkyl is optionally replacedwith a heteroatom selected from O and S.

It is another embodiment of the application that the optionalsubstituents on R¹ in the compounds of the formulae Ia, Ib and II areindependently selected from one or more of OH, halo, CN, NO₂, C₁₋₆alkyl,halo-substituted C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkoxy,C₂₋₈alkenyl, C₂₋₈alkenyloxy, aryl, aryloxy, aryl(C₁₋₄alkoxy),heteroaryl, heteroaryloxy, heteroaryl(C₁₋₄alkoxy), NH₂, NH(C₁₋₆alkyl),N(C₁₋₆alkyl)(C₁₋₆alkyl), C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl,SO₂NH₂, SO₂NHC₁₋₆alkyl and SC₁₋₄alkyl. Particularly, in an embodiment ofthe application, the optional substituents on R¹ in the compounds of theformulae Ia, Ib and II are independently selected from one to three ofOH, F, Cl, Br, CN, NO₂, CF₃, OCF₃, C₁₋₄alkyl, C₁₋₄alkoxy, phenyl,benzyl, benzyloxy and C(O)OC₁₋₄alkyl.

It is an embodiment of the application that R² to R⁶ in the compounds ofthe formulae Ia, Ib and III are independently selected from H,C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, aryl and heteroaryl, the latter 4 groupsbeing optionally substituted. In another embodiment of the application,one or more of the carbons in C₁₋₁₀alkyl or C₃₋₁₀cycloalkyl isoptionally replaced with a heteromoiety selected from O, S, N, NR⁷ andNR⁷R⁸, in which R⁷ and R⁸ are independently selected from H andC₁₋₆alkyl. Suitably, one or more of the carbons in C₁₋₁₀alkyl orC₃₋₈cycloalkyl is optionally replaced with a heteroatom selected from Oand S. In a particular embodiment of the application, R² to R⁶ in thecompounds of the formulae Ia, Ib and III are independently selected fromH and C₁₋₆alkyl. In a more particular embodiment of the application, R²to R⁶ in the compounds of the formulae Ia, Ib and III are independentlyselected from H and methyl.

In another embodiment of the application, the optional substituents onR² to R⁶ in the compounds of the formulae Ia, Ib and III areindependently selected from one or more of OH, halo, CN, NO₂, C₁₋₆alkyl,halo-substituted C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkoxy,C₂₋₆alkenyl, C₂₋₆alkenyloxy, aryl, aryloxy, aryl(C₁₋₄alkoxy),heteroaryl, heteroaryloxy, heteroaryl(C₁₋₄alkoxy), NH₂, NH(C₁₋₆alkyl),N(C₁₋₆alkyl)(C₁₋₆alkyl), C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl,SO₂NH₂, SO₂NHC₁₋₆alkyl and SC₁₋₄alkyl.

In an embodiment of the application, the method of preparing compoundsof the formulae Ia and/or Ib is performed in the presence of ammonia. Inyet another embodiment of the application, the method of preparingcompounds of the formulae Ia and/or Ib is performed in the presence ofan ammonia salt NH₄ ⁺X⁻ in which X is an anionic counterion. In afurther embodiment of the application, X is selected from halo, R⁹COO,R⁹SO₄ and BF₄, in which R⁹ is selected from C₁₋₁₀alkyl, C₃₋₂₀cycloalkyl,aryl and heteroaryl, all of which are optionally substituted. In anembodiment of the application, X is Cl or Br. In a still furtherembodiment of the application, the optional substituents on R⁹ areindependently selected from one or more of OH, halo, CN, NO₂, phenyl,benzyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkoxy, C₁₋₆alkyl,halo-substituted C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkenyloxy, NH₂,NH(C₁₋₆alkyl), N(C₁₋₆alkyl)(C₁₋₆alkyl), C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl,SO₂C₁₋₆alkyl, SO₂NH₂, SO₂NHC₁₋₆alkyl and SC₁₋₄alkyl.

In an embodiment of the application, the method of preparing compoundsof formulae Ia and/or Ib is performed in a suitable solvent. Moreparticularly, the solvent is selected from selected from selected frommethanol, ethanol, propanol, butanol, toluene, tetrahydrofuran,acetonitrile, benzene, dioxane, methylene chloride, liquid ammonia,ionic liquids and mixtures thereof.

In an embodiment of the application, the method of preparing compoundsof formulae Ia and/or Ib is performed by combining an alcoholic solutionof ammonia, or an ammonia equivalent in a suitable solvent, with thecompound of formula II. The ammonia or ammonia equivalent is suitablyused in molar excess amounts, for example about 5 to about 20 molarequivalents, relative to the amount of the compound of formula II. Oncethe ammonia or ammonia equivalent has reacted with the compound offormula II for a sufficient period of time (determinable by a personskilled in the art, for example by following the reaction using thinlayer chromatography and observing the disappearance of the compound offormula II), the compound of formula III may be added to the combinedsolution of ammonia or ammonia equivalent and compound of formula II.The compound of formula III may be used in molar excess amounts, forexample about 1.1 to about 5 molar equivalents, suitably about 1.2 to2.5 molar equivalents, relative to the amount of the compound of formulaII.

It is an embodiment of the application that the method of preparingcompounds of formulae Ia and/or Ib is performed at room temperature orabove or below room temperature, for example, at a temperature of from−40° C. to +100° C., suitably from 0° C. to 50° C., more suitably from10° C. to 30° C. In an embodiment of the application, the method isperformed at room temperature.

A person skilled in the art would appreciate that the reactionconditions, including for example, temperature, time and reactantratios, may vary depending on a number of variables, including, but notlimited to, the structure of the starting materials (compounds offormulae II and III), the solvent, presence or absence of a catalyst(vide supra) and the reaction pressure. A person skilled in the artwould be able to optimize the reaction conditions to obtain the bestyields and overall performance of the reaction based on the resultspresented herein and methods known in the art. Reaction progress may bemonitored using known techniques, for example, thin layerchromatography, high performance liquid chromatography and/or NMRspectroscopy, to determine optimum reaction conditions.

The compounds of the formulae Ia and/or Ib may optionally be isolatedusing standard methods known in the art, for example, by acid/baseextraction methods. Further purification steps may be performed, forexample, chromatography, and if R² and R³ are different, chiralresolution. Chiral resolution of enantiomers may be performed, forexample, by forming chiral esters or salts, followed by separation ofthe diastereomers using crystallization or chromatographic techniques,and liberation of the free amine.

A new method for the preparation of secondary carbinamine compounds fromthe diastereoselective arylation of aldehydes in the presence of ammoniahas also been developed. The method has been shown to provide the arylamines in high yields through simple acid-base extraction. Accordingly,in another aspect, the present application relates to a method ofpreparing an amine of the formula IV:

whereinR¹ is selected from C₁₋₂₀alkyl, C₁₋₂₀alkoxy, C₂₋₂₀alkenyl, C₂₋₂₀alkynyl,C₃₋₂₀cycloalkyl, C₃₋₂₀cycloalkoxy, aryl, aryloxy, heteroaryl andheteroaryloxy, all of which are optionally substituted and one or moreof the carbons in C₁₋₂₀alkyl, C₁₋₂₀alkoxy, C₂₋₂₀alkenyl, C₂₋₂₀alkynyl,C₃₋₂₀cycloalkyl or C₃₋₂₀cycloalkoxy is optionally replaced with aheteromoiety selected from O, S, N, NR⁷ and NR⁷R⁸;R¹⁰ is aryl or heteroaryl, both of which are optionally substituted; andR⁷ and R⁸ are independently selected from H, C₁₋₂₀alkyl, C₂₋₂₀alkynyl,C₃₋₂₀cycloalkyl, aryl and heteroaryl, the latter 4 groups beingoptionally substituted;comprising reacting a compound of the formula II:

wherein R¹ is as defined for the compounds of formula IV, with acompound of the formula V:

wherein R¹⁰ is as defined for the compound of formula IV, in thepresence of ammonia NH₃ or an ammonia equivalent of the formula NH₄ ⁺X⁻,wherein X is an anionic counterion, and optionally isolating the amineof the formula IV.

It is an embodiment of the application that R¹ in the compounds of theformulae II and IV is selected from C₁₋₁₀alkyl, aryl and heteroaryl, allof which are optionally substituted. In another embodiment of theapplication, one or more of the carbons in C₁₋₁₀alkyl is optionallyreplaced with a heteromoiety selected from O, S, N, NR⁷ and NR⁷R⁸, inwhich R⁷ and R⁸ are independently selected from H and C₁₋₆alkyl.Suitably, one or more of the carbons in C₁₋₁₀alkyl is optionallyreplaced with a heteroatom selected from O and S.

In an embodiment of the application, the optional substituents on R¹ inthe compounds of the formulae II and IV are independently selected fromone or more of OH, halo, CN, NO₂, C₁₋₆alkyl, halo-substituted alkyl,C₁₋₆alkoxy, halo-substituted alkoxy, C₂₋₆alkenyl, C₂₋₆alkenyloxy, aryl,aryloxy, aryl(C₁₋₄alkoxy), heteroaryl, heteroaryloxy,heteroaryl(C₁₋₄alkoxy), NH₂, NH(C₁₋₆alkyl), N(C₁₋₆alkyl)(C₁₋₆alkyl),C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl, SO₂NH₂, SO₂NHC₁₋₆alkyl andSC₁₋₄alkyl. More particularly, in an embodiment of the application, theoptional substituents on R¹ in the compounds of the formulae II and Vare independently selected from one to three of OH, F, Cl, Br, CN, NO₂,CF₃, OCF₃, C₁₋₄alkyl, C₁₋₄alkoxy, phenyl, benzyl, benzyloxy andC(O)OC₁₋₄alkyl.

It is an embodiment of the application that R¹⁰ in the compounds of theformulae IV and V is selected from phenyl, naphthyl, anthraceneyl,1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl,indenyl, furanyl, thienyl, pyrrolo, pyridyl, indolo and benzofuranyl,all of which are optionally substituted. In a particular embodiment ofthe application, R¹⁰ in the compounds of the formulae IV and V isoptionally substituted phenyl.

In an embodiment of the application, the optional substituents on R¹⁰ inthe compounds of the formulae IV and V are independently selected fromone or more of OH, halo, CN, NO₂, C₁₋₆alkyl, halo-substituted alkyl,C₁₋₆alkoxy, halo-substituted alkoxy, C₂₋₆alkenyl, C₂₋₆alkenyloxy, aryl,aryloxy, aryl(C₁₋₄alkoxy), heteroaryl, heteroaryloxy,heteroaryl(C₁₋₄alkoxy), NH₂, NH(C₁₋₆alkyl), N(C₁₋₆alkyl)(C₁₋₆alkyl),C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl, SO₂NH₂, SO₂NHC₁₋₆alkyl andSC₁₋₄alkyl. Particularly, in an embodiment of the application, theoptional substituents on R¹⁰ in the compounds of the formulae IV and Vare independently selected from on to three of OH, F, Cl, Br, CN, NO₂,CF₃, OCF₃, C₁₋₄alkyl, C₁₋₄alkoxy, phenyl, benzyl, benzyloxy andC(O)OC₁₋₄alkyl.

In an embodiment of the application, the method of preparing compoundsof formula IV is performed in the presence of ammonia. In yet anotherembodiment of the application, the method of preparing compounds offormula IV is performed in the presence of an ammonia salt NH₄ ⁺X⁻ inwhich X is an anionic counter ion. In a further embodiment of theapplication, X is selected from halo, R⁹COO, R⁹SO₄ and BF₄, in which R⁹is selected from C₁₋₁₀alkyl, C₃₋₂₀cycloalkyl, aryl and heteroaryl, allof which are optionally substituted. In an embodiment of theapplication, X is Cl or Br. In a still further embodiment of theapplication, the optional substituents on R⁹ are independently selectedfrom one or more of OH, halo, CN, NO₂, phenyl, benzyl, C₁₋₆alkoxy,halo-substituted alkoxy, C₁₋₆alkyl, halo-substituted alkyl, C₂₋₆alkenyl,C₂₋₆alkenyloxy, NH₂, NH(C₁₋₆alkyl), N(C₁₋₆alkyl)(C₁₋₆alkyl),C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl, SO₂NH₂, SO₂NHC₁₋₆alkyl andSC₁₋₄alkyl.

In an embodiment of the application, the method of preparing compoundsof formula IV is performed in a solvent. More particularly, the solventis selected from selected from methanol, ethanol, propanol, butanol,toluene, tetrahydrofuran, acetonitrile, benzene, dioxane, methylenechloride, liquid ammonia, ionic liquids and mixtures thereof.

In an embodiment of the application, the method of preparing compoundsof formula IV is performed by combining an alcoholic solution ofammonia, or an ammonia equivalent in a suitable solvent, with thecompound of formula II. The ammonia or ammonia equivalent is suitablyused in molar excess amounts, for example about 5 to about 20 molarequivalents, relative to the amount of the compound of formula II. Oncethe ammonia or ammonia equivalent has reacted with the compound offormula II for a sufficient period of time (determinable by a personskilled in the art, for example by following the reaction using thinlayer chromatography and observing the disappearance of the compound offormula II), the compound of formula III may be added to the combinedsolution of ammonia or ammonia equivalent and compound of formula II.The compound of formula V may be used in molar excess amounts, forexample about 1.1 to about 5 molar equivalents, suitably about 1.2 to2.5 molar equivalents, relative to the amount of the compound of formulaII.

In another embodiment of the present application, the method ofpreparing compounds of formula IV is performed at a temperature of fromabout −40° C. to about +150° C. More suitably, in an embodiment of theapplication, the method is performed at a temperature of from about +50°C. to about +120° C. It is an embodiment of the application that themethod is performed at a temperature of about 80° C.

A person skilled in the art would appreciate that the reactionconditions, including for example, temperature, time and reactantratios, may vary depending on a number of variables, including, but notlimited to, the structure of the starting materials (compounds offormulae II and V), the solvent, presence or absence of a catalyst andthe reaction pressure. A person skilled in the art would be able tooptimize the reaction conditions to obtain the best yields and overallperformance of the reaction based on the results presented herein andmethods known in the art. Reaction progress may be monitored using knowntechniques, for example, thin layer chromatography, high performanceliquid chromatography and/or NMR spectroscopy, to determine optimumreaction conditions.

The compounds of the formula IV may optionally be isolated usingstandard methods known in the art, for example, by acid/base extractionmethods. Further purification steps may be performed, for example,chromatography, and if R¹ and R¹⁰ are different, chiral resolution.Chiral resolution of enantiomers may be performed, for example, byforming chiral esters or salts, followed by separation of thediastereomers using crystallization or chromatographic techniques, andliberation of the free amine.

It is an embodiment of the application that the methods for preparingcompounds of formula Ia, Ib and/or IV are performed in the presence of acatalyst, in particular a transition metal catalyst. Particularly, in anembodiment of the application, the catalyst is any of the well-knowntransition metal catalysts. In a further embodiment of the application,the metal is selected from rhodium, ruthenium, iridium, copper,platinum, palladium and nickel. In a still further embodiment of theapplication, the metal is rhodium. The catalyst may be included in themethod, for example, by adding it along with the compound of formula IIIor V, either by a separate addition or in a combined solution with thecompound of formula III or V.

In an embodiment of the present application, when a catalyst is used, itis added in amounts of about 1 mol % to about 20 mol %, suitably about 5mol % to about 10 mol %, based on the amount of the aldehyde.

In another embodiment of the application, the metal catalyst possessesat least one chiral or achiral ligand. In another embodiment, the ligandis a phosphine, diphosphine, aminophosphine, carbene, amine or oxazolineligand. Transition metal catalysts containing chiral ligands are wellknown in the art and include those used for stereoselectivehydrogenations, transmetalation and other bond forming reactions [a)Transition metals for organic synthesis, ed. M. Beller and C. Bolm,Wiley-VCH, New York, 2nd edn, 2005; b) J. Tsuji in Transition metalreagents and catalysts: innovations in organic synthesis, John Wiley &Sons, New York, 2000]. By performing the methods described herein in thepresence of a chiral catalyst, stereoselective additions of thecompounds of formula II to the compounds of formula III, or thecompounds of formulae II to the compounds of formula V, are achieved.Accordingly, compounds of formulae Ia, Ib and IV may be prepared inenantioselective and/or diastereoselective manner. In an embodiment,when a transition metal catalysts comprising a chiral ligand is used, anenantiomerically or diasteromerically enriched compound is obtained,i.e. one enantiomer or diastereomer will be present in an amount greaterthan 50%. In a further embodiment, one enantiomer or diastereomer willbe present in an amount greater than 60%. In another embodiment, oneenantiomer or diastereomer will be present in an amount greater than70%. In a further embodiment, one enantiomer or diastereomer will bepresent in an amount greater than 80%. In yet a further embodiment, oneenantiomer or diastereomer will be present in an amount greater than90%. In another embodiment, one enantiomer or diastereomer will bepresent in an amount greater than 95%. In an embodiment, one enantiomeror diastereomer will be present in an amount greater than 99%.

The following non-limiting examples are illustrative of the presentapplication:

EXAMPLES Materials and Methods

All reagents were used as received (Aldrich, Acros, Strem). Methanol wasdried over magnesium methoxide and distilled prior to use. Allyl (E)-and (Z)-crotylboronic acid in anhydrous methanol (2 M solution) wereprepared just prior to use (exact molarities were confirmed by titrationwith benzaldehyde) [H. C. Brown, U. S. Racherla and P. J. Pellechia, J.Org. Chem., 1990, 55, 1868].

Melting points were uncorrected and were measured on a Fisher-Johnsmelting point apparatus. ¹H and ¹³C NMR were recorded at 300 or 500 MHzand 75 or 125 MHz respectively on a Bruker Spectrospin 300 or 500 MHzspectrometer. Proton chemical shifts were internally referenced to theresidual proton resonance in CDCl₃ (δ 7.26). Carbon chemical shifts wereinternally referenced to the deuterated solvent signals in CDCl₃ (δ77.00). Infrared spectra were obtained on a Bruker VECTOR22FT-IRspectrometer. HRMS-Cl and HRMS-ESI were performed on a Waters/MicromassGCT time-of-flight mass spectrometer and a Waters/Micromass Q-TOF Globalquadrupole time-of-flight mass spectrometer respectively.

Example 1 General Procedure for the Allylation of Aldehydes withAllylboronic Acid in the Presence of Ammonia

A solution of ammonia (ca. 7N in MeOH, 0.75 mmol, ca. 10 equiv.) wasadded to the aldehyde (1) (0.5 mmol). The resulting solution was stirredfor 15 minutes at room temperature, followed by the addition of afreshly prepared solution of allylboronic acid (2) (2M in MeOH, 0.4 mL,0.80 mmol) dropwise over 5 minutes. The reaction mixture wassubsequently stirred for 1 hour at room temperature. The volatiles wereremoved in vacuo and the residue re-dissolved in Et₂O (15 mL). AqueousHCl (1N, 15 mL) was then added dropwise to the residue. The biphasicmixture was vigorously shaken, and the layers were separated. The acidicaqueous layer was washed with Et₂O (3×15 mL), and made basic by theaddition of solid NaOH (ca. 5 g). The aqueous layer was then extractedwith CH₂Cl₂ (3×15 mL). The combined organic extracts were dried withNa₂SO₄, filtered and concentrated in vacuo to afford the desiredsecondary carbinamine (3). Table 1 summarizes the various aldehydes thatwere converted to carbinamines and the respective yields.

(i) 1-(Benzyloxy)pent-4-en-2-amine (3a)

3a isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 300 MHz) δ7.32-7.20 (5H, m), 5.84-5.67 (1H, m), 5.12-5.00 (2H, m), 4.83 (2H, s),3.41 (1H, dd, J=9.0, 4.5 Hz), 3.24 (1H, dd, J=9.0, 7.5 Hz), 3.08-2.97(1H, m), 2.25-2.15 (1H, m), 2.08-1.94 (1H, m), 1.37 (2H, br s); ¹³C NMR(CDCl₃, 75 MHz) δ 138.09, 134.98, 128.10, 127.35, 127.32, 117.16, 75.07,72.95, 50.15, 38.59; HRMS (ESI) m/z calcd. for C₁₂H₁₈NO (MH⁺) 192.1388,found 192.1384.

(ii) 1-(4-Methoxyphenyl)but-3-en-1-amine (3b)

3b isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 300 MHz) δ 7.23(2H, d, J=8.5 Hz), 6.84 (2H, d, J=8.5 Hz), 5.80-5.64 (1H, m), 5.13-5.00(2H, m), 3.92 (1H, dd, J=8.0, 5.5 Hz), 3.76 (3H, s), 2.46-2.24 (2H, m),1.48 (2H, br s); ¹³C NMR (CDCl₃, 75 MHz) δ 158.41, 137.89, 135.49,127.18, 117.30, 113.60, 5.08, 54.65, 44.17; HRMS (Cl) m/z calcd. forC₁₁H₁₆NO (MH⁺) 178.1232, found 178.1227.

(iii) Undec-1-en-4-amine (3c)

3c isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 300 MHz) δ5.82-5.65 (1H, m), 5.09-4.98 (2H, m), 2.77-2.68 (1H, m), 2.23-2.12 (1H,m), 1.99-1.88 (1H, m), 1.43-1.15 (14H, m), 0.84 (3H, t, J=7.0 Hz); ¹³CNMR (CDCl₃, 75 MHz) δ 135.92, 117.06, 50.53, 42.56, 27.65, 31.77, 29.65,29.23, 26.19, 22.58, 14.01; HRMS (Cl) m/z calcd. for C₁₁H₂₄N (MH⁺)170.1909, found 170.1905.

(iv) 2,2-dimethylhex-5-en-3-amine (3d)

3d isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 500 MHz) δ5.83-5.73 (1H, m), 5.06 (1H, dd, J=17.0, 1.5 Hz), 5.04 (1H, dd, J=10.0,1.5 Hz), 2.42 (1H, dd, J=10.5, 2.5 Hz), 2.38-2.30 (1H, m), 1.76-1.67(1H, m), 1.11 (2H, br s), 0.87 ((9H, s); ¹³C NMR (CDCl₃, 125 MHz) δ137.71, 116.62, 59.47, 36.87, 26.09; HRMS (Cl) m/z calcd. for C₈H₁₈N(MH⁺) 128.1439, found 128.1437.

(v) 1-phenylhex-5-en-3-amine (3e)

3e isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 300 MHz) δ7.31-7.09 (5H, m), 5.87-5.69 (1H, m), 5.10 (1H, d, J=17.0 Hz), 5.09 (1H,d, J=11.0 Hz), 2.90-2.55 (3H, m), 2.33-2.20 (1H, m), 2.03 (1H, dt,J=13.5, 7.5 Hz), 1.83-1.55 (2H, m), 1.29 (2H, br s); ¹³C NMR (CDCl₃, 75MHz) δ 142.18, 135.57, 128.29 (two signals overlapped), 125.70, 117.38,50.10, 42.59, 39.31, 32.58.

(vi) 1-cyclohexylbut-3-en-1-amine (3f)

3f isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 300 MHz) δ 5.73(1H, dddd, J=17.0, 10.5, 8.0, 6.0 Hz), 5.01 (1H, d, J=17.0 Hz), 4.99(1H, d, J=10.5 Hz), 2.53-2.43 (1H, m), 2.25-2.15 (1H, m), 1.88 (1H, dt,J=13.5, 8.5 Hz), 1.64-1.42 (5H, m), 1.24-0.87 (8H, m); ¹³C NMR (CDCl₃,75 MHz) δ 136.65, 116.94, 55.30, 43.47, 39.46, 29.68, 28.28, 26.62,26.49, 26.37.

(vii) 1-(3-methoxyphenyl)but-3-en-1-amine (3g)

3g isolated as a low melting point solid: m.p.=30° C. (EtOAc); ¹H NMR(CDCl₃, 300 MHz) δ 7.23 (1H, t, J=8.5 Hz), 6.95-6.87 (2H, m), 6.77 (1H,ddd, J=8.5, 2.5, 1.0 Hz), 5.74 (1H, dddd, J=17.0, 10.0, 8.0, 6.5 Hz),5.11 (1H, J=17.0 Hz), 5.07 (1H, d, J=10.0 Hz), 4.00-3.92 (1H, m), 3.79(3H, s), 2.45 (1H, dt, J=13.5, 6.0 Hz), 2.31 (1H, dt, J=13.5, 8.0 Hz),1.57 (2H, br s); ¹³C NMR (CDCl₃, 75 MHz) δ 159.67, 147.60, 135.36,129.32, 118.61, 117.56, 112.25, 111.84, 55.28, 55.13, 44.09.

(viii) 4-(1-aminobut-3-enyl)benzonitrile (3h)

3h isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 300 MHz) δ 7.54(1H, d, J=8.5 Hz), 7.41 (1H, d, J=8.5 Hz), 5.65 (1H, dddd, J=17.5, 10.5,8.0, 6.5 Hz), 5.10-4.98 (2H, m), 4.01 (1H, dd, J=8.0, 5.5 Hz), 2.36 (1H,ddd, J=14.0, 6.5, 5.5 Hz), 2.26 (1H, dt, J=14.0, 8.0 Hz), 1.52 (2H, brs); ¹³C NMR (CDCl₃, 75 MHz) δ 151.35, 134.44, 132.22, 127.29, 118.98,118.46, 110.67, 55.06, 44.03.

(ix) 1-(pyridin-2-yl)but-3-en-1-amine (3i)

3i isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 300 MHz) δ 8.47(1H, br s), 7.54 (1H, dt, J=7.5, 1.5 Hz), 7.22 (1H, d, J=8.0 Hz), 7.05(1H, dd, J=7.5, 5.5 Hz), 5.69 (1H, dddd, J=17.5, 10.0, 7.5, 6.5 Hz),5.01 (1H, d, J=17.5 Hz), 4.98 (1H, d, J=10.0 Hz), 3.96 (1H, t, J=7.5Hz), 2.57-2.44 (1H, m), 2.30 (1H, dt, J=13.5, 8.0 Hz), 1.71 (2H, br s);¹³C NMR (CDCl₃, 75 MHz) δ 163.95, 148.95, 136.21, 135.02, 121.71,120.76, 117.54, 56.32, 43.09.

(x) 1-(1H-indol-3-yl)but-3-en-1-amine (3j)

3j isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 300 MHz) d8.94(1H, br s), 7.73 (1H, d, J=7.5 Hz), 7.31 (1H, d, J=8.0 Hz), 7.24-7.10(2H, m), 7.02 (1H, d, J=2.0 Hz), 5.96-5.80 (1H, m), 5.25-5.10 (2H, m),4.41 (1H, dd, J=8.0, 5.0 Hz), 2.80-2.69 (1H, m), 2.60-2.47 (1H, m), 1.80(2H, br s); ¹³C NMR (CDCl₃, 75 MHz) d 136.47, 135.83, 125.83, 121.77,120.66, 120.26, 119.10, 118.95, 117.38, 111.29, 47.91, 42.98.

Discussion

The addition of allylboronic acid (2) to aldehydes, when firstpretreated with ammonia, has been found to lead cleanly and efficientlyto the formation of the corresponding secondary carbinamines under mildreaction conditions. As seen in Table 1, the resulting secondarycarbinamines were easily isolated and uniformly obtained in high yieldsthrough standard acid-base extraction, and did not require anysubsequent chromatographic purification.

Example 2 General Procedure for the Crotylation of Aldehydes with (E) or(Z)-Crotylboronic Acid in the Presence of Ammonia

A solution of ammonia (ca. 7N in MeOH, 0.75 mmol, ca. 10 equiv.) wasadded to the aldehyde (1) (0.5 mmol). The resulting solution was stirredfor 15 minutes at room temperature, followed by the addition of afreshly prepared solution of either (E) or (Z)-crotylboronic acid (4a)or (4b) (2M in MeOH, 0.4 mL, 0.80 mmol) dropwise over 5 minutes. Thereaction mixture was subsequently stirred for 1 hour at roomtemperature. The volatiles were removed in vacuo and the residuere-dissolved in Et₂O (15 mL). Aqueous HCl (1N, 15 mL) was then addeddropwise to the residue. The biphasic mixture was vigorously shaken, andthe layers were separated. The acidic aqueous layer was washed with Et₂O(3×15 mL), and made basic by the addition of solid NaOH (ca. 5 g). Theaqueous layer was then extracted with CH₂Cl₂ (3×15 mL). The combinedorganic extracts were dried with Na₂SO₄, filtered and concentrated invacuo to afford the desired secondary carbinamine (5). Table 2summarizes the various aldehydes that were converted to carbinaminesusing (E) or (Z)-crotylboronic acid and the respective yields anddiastereomeric ratios (d.r.).

(i) (2S,3S)-1-(benzyloxy)-3-methylpent-4-en-2-amine (5a)

5a isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 300 MHz) δ7.35-7.22 (5H, m), 5.78-5.65 (1H, m), 5.09-5.00 (2H, m), 4.51 (2H, brs), 3.50 (1H, dd, J=9.0, 4.0 Hz), 3.32 (1H, dd, J=9.0, 7.5 Hz),2.92-2.77 (1H, m), 2.23 (1H, hextet, J=7.0 Hz), 1.36 (2H, br s), 1.00(3H, d, J=7.0 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 140.70, 138.27, 128.25,127.52, 127.46, 115.34, 73.61, 73.16, 54.82, 41.15, 16.74; HRMS (Cl) m/zcalcd. for C₁₃H₂₀NO (MH⁺) 206.1545, found 206.1550.

(ii) (1S,2S)-1-(4-Methoxyphenyl)-2-methylbut-3-en-1-amine (5b)

5b isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 300 MHz) δ 7.20(2H, d, J=8.5 Hz), 6.83 (2H, d, J=8.5 Hz), 5.71 (1H, ddd, J=17.5, 10.0,8.5 Hz), 5.13 (1H, dd, J=17.5, 2.0 Hz), 5.07 (1H, dd, J=10.0, 2.0 Hz),3.76 (3H, s), 3.56 (1H, d, J=8.0 Hz), 3.29 (1H, hextet, J=7.0 Hz), 1.48(2H, br s), 0.78 (3H, d, J=7.0 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 158.46,141.76, 136.54, 128.07, 115.47, 113.42, 59.86, 55.01, 46.35, 17.49; HRMS(Cl) m/z calcd. for C₁₃H₂₀NO (MH⁺) 206.1545, found 206.1550.

(iii) (1S,2R)-1-(4-Methoxyphenyl)-2-methylbut-3-en-1-amine (5c)

(iv) (1S,2R)-1-(1H-indol-3-yl)-2-methylbut-3-en-1-amine (5d)

5d isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 500 MHz) d 8.82(1H, br s), 7.71 (1H, d, J=8.0 Hz), 7.32 (1H, d, J=8.0 Hz), 7.22 (1H, t,J=7.0 Hz), 7.16 (1H, t, J=7.0 Hz), 7.04 (1H, d, J=2.0 Hz), 5.94 (1H,ddd, J=17.5, 10.5, 7.0 Hz), 5.16 (1H, dd, J=17.5, 1.5 Hz), 5.10 (1H, dd,J=10.5, 1.5 Hz), 4.37 (1H, d, J=5.0 Hz), 2.78 (1H, J=5.5 Hz), 1.68 (2H,br s), 1.07 (3H, d, J=7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz) d 141.75,136.37, 126.40, 121.70, 121.59, 119.35, 119.18, 119.09, 114.61, 111.18,52.87, 43.69, 14.72.

Discussion

The addition of (E) or (Z)-crotyltrifluoroborate (4a) or (4b) toaldehydes, when first pretreated with ammonia, has been found to leadcleanly and efficiently to the formation of the corresponding secondarycarbinamines under mild reaction conditions as seen in Table 2.Excellent diastereoselectivities were observed with all the testedsubstrates, in which the (E)-crotyl reagent (4a) afforded theanti-homoallylic amine, and the (Z)-crotyl reagent (4b) afforded thesyn-homoallylic amine. The resulting secondary carbinamines were easilyisolated and uniformly obtained in high yields through standardacid-base extraction, and did not require any subsequent purification.

Example 3 General Procedure for the Rhodium-Catalyzed Addition of Aryland Alkenylboronic Acids to Aldehydes in the Presence of Ammonia

A saturated solution of ammonia in 1,4-dioxane (2 mL) was added to thealdehyde (6). To the resulting solution was added freshly preparedboronic acid (8) (1.0 mmol) and Rh(acac)(CO)₂ (12.9 mg, 0.05 mmol).Distilled water (0.4 mL) was then added to the solution and the reactionmixture was heated to 80° C. in a sealed tube for 16 h. The reactionmixture was then cooled to room temperature and the volatiles wereremoved in vacuo. The residue was dissolved in CH₂Cl₂ (20 mL) and washedwith saturated aq. NaHCO₃ (10 mL). The organic layer was dried (Na₂SO₄),filtered and concentrated in vacuo to afford a yellow oil, which wasthen subjected to silica gel chromatography (EtOAc/hexanes/Et₃N) toafford the carbinamine (8). In some cases, the resulting carbinamine (8)was treated with HCl (1.0 Min Et₂O) to afford the correspondinghydrochloride salt. The salt was then isolated by filtration.

(i) (4-bromophenyl)(phenyl)methanamine (8a)

8a isolated as a clear, colourless oil. ¹H NMR (CD₃OD, 300 MHz) d 7.55(2H, d, J=8.5 Hz), 7.50-7.13 (7H, m), 5.48 (1H, s), 1.80 (2H, br s).

(ii) Phenyl(4-(trifluoromethyl)phenyl)methanaminium chloride (8b)

8b isolated as a white solid: mp=231-234° C.; ¹H NMR (500 MHz, CD₃OD) δ7.78 (2H, d, J=8.0 Hz), 7.64 (1H, s), 7.62 (1H, d, J=0.5 Hz), 7.51-7.41(5H, m), 5.79 (1H, s); ¹³C NMR (125 MHz, CD₃OD) δ 143.04, 138.05, 132.31(q, J=32.0 Hz), 130.73, 130.50, 129.33, 128.78, 127.46 (q, J=4.0 Hz),59.04.

(iii) naphthalen-2-yl(p-tolyl)methanaminium chloride (8c)

8c isolated as a white solid: mp=234-236° C.; ¹H NMR (300 MHz, CD₃OD) δ7.97-7.90 (4H, m), 7.60-7.56 (2H, m), 7.47 (1H, dd, J=9.0, 2.0 Hz), 7.38(2H, d, J=8.5 Hz), 7.31 (2H, d, J=8.0 Hz), 5.80 (1H, s), 2.39 (3H, s);¹³C NMR (75 MHz, CD₃OD) δ 138.90, 134.79, 134.24, 133.24, 129.52,128.88, 127.94, 127.87, 127.46, 127.14, 126.73, 126.64, 125.86 124.38,58.05, 19.83.

(iv) (4-chlorophenyl)(phenyl)methanaminium chloride (8d)

8d isolated as a white solid: m.p.=220-224° C.; ¹H NMR (300 MHz, CD₃OD)δ 7.48 (9H, s), 5.71 (1H, s); ¹³C NMR (75 MHz, CD₃OD) δ 144.81, 136.92,136.13, 134.51, 129.06, 128.97, 128.83, 128.74, 127.00, 120.26, 57.43.

Discussion:

The addition of aryl boronic acids (7) to aldehydes (6), when firstpretreated with ammonia, led cleanly and efficiently to the formation ofthe corresponding secondary carbinamines under mild reaction conditionsas seen in Table 3. The resulting secondary carbinamines were easilyisolated and uniformly obtained in good yields.

Example 4 General Procedure for the Enantioselective Rhodium-CatalyzedAddition of Aryl- and Alkenylboronic Acids to Aldehydes in the Presenceof Ammonia

A saturated solution of ammonia in 1,4-dioxane (2 mL) was added to thealdehyde. To the resulting solution was added freshly prepared boronicacid (1.0 mmol), Rh(acac)(CO)₂ (6.5 mg, 0.025 mmol) and (2S,5S)-Duphos(8 mg, 0.025 mmol). Distilled and degassed water (0.4 mL) was then addedto the solution and the reaction mixture was heated to 80° C. in asealed tube for 16 h. The reaction mixture was then cooled to roomtemperature and the volatiles were removed in vacuo. The residue wasdissolved in CH₂Cl₂ (20 mL) and washed with saturated aq. NaHCO₃ (10mL). The organic layer was dried (Na₂SO₄), filtered and concentrated invacuo to afford a yellow oil, which was then subjected to silica gelchromatography (EtOAc/hexanes/Et₃N) to afford the carbinamine (9). Theenantioselectivities were measured by chiral HPLC. In some cases, theresulting carbinamine (9) was treated with HCl (1.0 Min Et₂O) to affordthe corresponding hydrochloride salt. The salt was then isolated byfiltration.

(i) (4-methoxyphenyl)(phenyl)methanamine (9a)

9a isolated as a clear, pale yellow oil: ¹H NMR [300 MHz, (CD₃)₂SO] δ7.40-7.10 (7H, m), 6.85 (2H, dd, J=7.0, 2.0 Hz), 5.02 (1H, s), 3.70 (3H,s), 2.08 (2H, br s); optical rotation α_(D) ²¹=10.9° (c=1.00, MeOH)

(ii) (4-methoxyphenyl)(p-tolyl)methanaminium chloride (9b)

9b was isolated as a white solid: m.p. (Et₂O)=257-260° C.; ¹H NMR (300MHz, CD₃OD) δ 7.50-7.39 (5H, m), 7.33-7.22 (4H, m), 5.60 (1H, s), 4.98(3H, br s), 2.33 (3H, s); ¹³C NMR (75 MHz, CD₃OD) δ 140.23, 138.71,135.62, 130.83, 130.27, 129.95, 128.33, 59.18, 21.11; optical rotationα_(D) ²¹=65.7° (c=1.00, MeOH)

(iii) (4-fluorophenyl)(4-methoxyphenyl)methanamine (9c)

(iv) (4-methoxyphenyl)(phenyl)methanamine (9d)

(v) phenyl(p-tolyl)methanamine (9e)

(vi) (4-fluorophenyl)(phenyl)methanaminium chloride (9f)

9f isolated as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.50-7.42 (7H,m), 7.25-7.15 (2H, m), 5.72 (1H, s), 4.94 (3H, br s).

Discussion

The addition of aryl boronic acids to aldehydes in the presence of arhodium catalyst and DUPHOS, when first pretreated with ammonia, hasbeen found to lead cleanly and enantioselectively to the formation ofthe corresponding secondary carbinamines under mild reaction conditionsas seen in Table 4. The resulting secondary carbinamines were easilyisolated and uniformly obtained in good yields.

TABLE 1 Reaction of aldehydes with allylboronic acid in the presence ofammonia

entry R yield (%) 3a PhCH₂OCH₂ 93 3b 4-CH₃OC₆H₄ 91 3c n-C₇H₁₅ 90 3d t-Bu82 3e PhCH₂CH₂ 95 3f Cyclohexyl 87 3g 3-CH₃OC₆H₄ 84 3h 4-NCC₆H₄ 86 3i2-Pyridyl 70 3j 3-Indolyl 72

TABLE 2 Reaction of aldehydes with (E)- or (Z)-crotylboronic acids inthe presence of ammonia

entry R reagent d. r. yield (%) 5a PhCH₂OCH₂ 4a 95:5 81 5b 4-CH₃OC₆H₄ 4a96:4 89 5c 4-CH₃OC₆H₄ 4b 96:4 91 5d 3-Indolyl 4b 95:5 79

TABLE 3 Rhodium catalyzed addition of aryl boronic acids to aldehydes inthe presence of ammonia

entry R¹ R² yield (%) 8a 4-BrC₆H₄ Ph 56 8b Ph 4-F₃CC₆H₄ 70 8c 4-CH₃C₆H₄2-Naphthyl 66 8d Ph 4-ClC₆H₄ 79

TABLE 4 Rhodium catalyzed enantioselective addition of arylboronic acidsto aldehydes in the presence of ammonia

entry R¹ R² yield (%) ee (%) 9a 4-MeOC₆H₄ Ph 65 39 9b 4-MeOC₆H₄4-CH₃C₆H₄ 68 43 9c 4-MeOC₆H₄ 4-FC₆H₄ 70 48 9d Ph 4-MeOC₆H₄ 61 45 9e Ph4-MeC₆H₄ 64 49 9f Ph 4-FC₆H₄ 74 52

1. A method of preparing a secondary amine of the formula Ia and/or Ib:

wherein R¹ is selected from C₁₋₂₀alkyl, C₁₋₂₀alkoxy, C₂₋₂₀alkenyl,C₂₋₂₀alkynyl, C₃₋₂₀cycloalkyl, C₃₋₂₀cycloalkoxy, aryl, aryloxy,heteroaryl and heteroaryloxy, all of which are optionally substitutedand one or more of the carbons in C₁₋₂₀alkyl, C₁₋₂₀alkoxy, C₂₋₂₀alkenyl,C₂₋₂₀alknyl, C₃₋₂₀cycloalkyl or C₃₋₂₀cycloalkoxy is optionally replacedwith a heteromoiety selected from O, S, N, NR⁷ and NR⁷R⁸; R² to R⁶ areindependently selected from H, C₁₋₂₀alkyl, C₁₋₂₀alkoxy, C₂₋₂₀alkenyl,C₂₋₂₀alkynyl, C₃₋₂₀cycloalkyl, C₃₋₂₀cycloalkoxy, aryl, aryloxy,heteroaryl and heteroaryloxy, the latter 9 groups being optionallysubstituted and one or more of the carbons in C₁₋₂₀alkyl, C₁₋₂₀alkoxy,C₂₋₂₀alkenyl, C₂₋₂₀alkynyl, C₃₋₂₀cycloalkyl or C₃₋₂₀cycloalkoxy isoptionally replaced with a heteromoiety selected from O, S, N, NR⁷ andNR⁷R⁸; R⁷ and R⁸ are independently selected from H, C₁₋₂₀alkyl,C₃₋₂₀cycloalkyl, aryl and heteroaryl, the latter 4 groups beingoptionally substituted; comprising reacting a compound of formula II:

wherein R¹ is as defined for the compounds of formula Ia and Ib, with acompound of formula III:

wherein R²-R⁶ are as defined for the compounds of formulae Ia and Ib, inthe presence of ammonia NH₃ or an ammonia equivalent of the formula NH₄⁺X⁻, wherein X is an anionic counterion, and optionally isolating theamine of the formula Ia and/or Ib.
 2. The method according to claim 1,wherein R¹ is selected from C₁₋₁₀alkyl, C₃₋₈cycloalkyl, aryl, andheteroaryl, all of which are optionally substituted and one or more ofthe carbons in C₁₋₁₀alkyl or C₃₋₈cycloalkyl is optionally replaced witha heteromoiety selected from O, S, N, NR⁷ and NR⁷R⁸, in which R⁷ and R⁸are independently selected from H and C₁₋₆alkyl.
 3. The method accordingto claim 2, wherein one or more of the carbons in C₁₋₁₀alkyl orC₃₋₈cycloalkyl is optionally replaced with a heteroatom selected from Oand S.
 4. The method according to claim 1, wherein the optionalsubstituents on R¹ in the compounds of the formulae Ia, Ib and II areindependently selected from one or more of OH, halo, CN, NO₂, C₁₋₆alkyl,halo-substituted C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkoxy,C₂₋₆alkenyl, C₂₋₆alkenyloxy, aryl, aryloxy, aryl(C₁₋₄alkoxy),heteroaryl, heteroaryloxy, heteroaryl(C₁₋₄alkoxy), NH₂, NH(C₁₋₆alkyl),N(C₁₋₆alkyl)(C₁₋₆alkyl), C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl,SO₂NH₂, SO₂NHC₁₋₆alkyl and SC₁₋₄alkyl.
 5. The method according to claim4, wherein the optional substituents on R¹ in the compounds of theformulae Ia, Ib and II are independently selected from one to three ofOH, F, Cl, Br, CN, NO₂, CF₃, OCF₃, C₁₋₄alkyl, C₁₋₄alkoxy, phenyl,benzyl, benzyloxy and C(O)OC₁₋₄alkyl.
 6. The method according to claim5, wherein the optional substituents on R¹ in the compounds of theformulae Ia, Ib and II are independently selected from one to three ofF, Cl, Br, C₁₋₄alkoxy and benzyloxy.
 7. The method according to claim 1,wherein R² to R⁶ in the compounds of the formulae Ia, Ib and III areindependently selected from H, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, aryl andheteroaryl, the latter 4 groups being optionally substituted and one ormore of the carbons in C₁₋₁₀alkyl or C₃₋₁₀cycloalkyl is optionallyreplaced with a heteromoiety selected from O, S, N, NR⁷ and NR⁷R⁸, inwhich R⁷ and R⁸ are independently selected from H and C₁₋₆alkyl.
 8. Themethod according to claim 7, wherein R² to R⁶ in the compounds of theformulae Ia, Ib and III are independently selected from H and C₁₋₆alkyl.9. The method according to claim 8, wherein R² to R⁶ in the compounds ofthe formulae Ia, Ib and III are independently selected from H andmethyl.
 10. The method according to claim 1, wherein the optionalsubstituents on R² and R⁶ in the compounds of the formulae Ia, Ib andIII are independently selected from one or more of OH, halo, CN, NO₂,C₁₋₆alkyl, halo-substituted C₁₋₆alkyl, C₁₋₆alkoxy, halo-substitutedC₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆alkenyloxy, aryl, aryloxy,aryl(C₁₋₄alkoxy), heteroaryl, heteroaryloxy, heteroaryl(C₁₋₄alkoxy),NH₂, NH(C₁₋₆alkyl), N(C₁₋₆alkyl)(C₁₋₆alkyl), C(O)C₁₋₆alkyl,C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl, SO₂NH₂, SO₂NHC₁₋₆alkyl and SC₁₋₄alkyl. 11.The method according to claim 1, wherein the method is performed in thepresence of ammonia.
 12. The method according to claim 1, wherein themethod is performed in the presence of an ammonia equivalent of theformula NH₄ ⁺X⁻, in which X is selected from halo, R⁹COO, R⁹SO₄ and BF₄and in which R⁹ is selected from C₁₋₁₀alkyl, C₃₋₂₀cycloalkyl, aryl andheteroaryl, all of which are optionally substituted.
 13. The methodaccording to claim 12, wherein X is Cl or Br.
 14. The method accordingto claim 13, wherein the optional substituents on R⁹ are independentlyselected from one or more of OH, halo, CN, NO₂, phenyl, benzyl,C₁₋₆alkoxy, halo-substituted C₁₋₆alkoxy, C₁₋₆alkyl, halo-substitutedalkyl, C₂₋₆alkenyl, C₂₋₆alkenyloxy, NH₂, NH(C₁₋₆alkyl),N(C₁₋₆alkyl)(C₁₋₆alkyl), C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl,SO₂NH₂, SO₂NHC₁₋₆alkyl and SC₁₋₄alkyl.
 15. The method according to claim1, wherein the method is performed in a solvent.
 16. The methodaccording to claim 15, wherein the solvent is selected from methanol,ethanol, propanol, butanol, toluene, tetrahydrofuran, acetonitrile,benzene, dioxane, methylene chloride, liquid ammonia, ionic liquids andmixtures thereof.
 17. The method according to claim 16, wherein thesolvent is methanol.
 18. The method according to claim 1, wherein themethod is performed at a temperature of from −40° C. to +100° C.
 19. Themethod according to claim 18, wherein the method is performed at roomtemperature.
 20. A method of preparing an amine of the formula IV:

wherein R¹ is selected from C₁₋₂₀alkyl, C₁₋₂₀alkoxy, C₂₋₂₀alkenyl,C₂₋₂₀alkynyl, C₃₋₂₀cycloalkyl, C₃₋₂₀cycloalkoxy, aryl, aryloxy,heteroaryl and heteroaryloxy, all of which are optionally substitutedand one or more of the carbons in C₁₋₂₀alkyl, C₁₋₂₀alkoxy, C₂₋₂₀alkenyl,C₂₋₂₀alkynyl, C₃₋₂₀cycloalkyl or C₃₋₂₀cycloalkoxy is optionally replacedwith a heteromoiety selected from O, S, N, NR⁷ and NR⁷R⁸; R¹⁰ is aryl orheteroaryl, both of which are optionally substituted; and R⁷ and R⁸ areindependently selected from H, C₁₋₂₀alkyl, C₂₋₂₀alkynyl,C₃₋₂₀cycloalkyl, aryl and heteroaryl, the latter 4 groups beingoptionally substituted; comprising reacting a compound of the formulaII:

wherein R¹ is as defined for the compounds of formula IV, with acompound of the formula V:

wherein R¹⁰ is as defined for the compound of formula IV, in thepresence of ammonia NH₃ or an ammonia equivalent of the formula NH₄ ⁺X⁻,wherein X is an anionic counterion, and optionally isolating thecompound of the formula IV.
 21. The method according to claim 20,wherein R¹ in the compounds of the formulae II and IV is selected fromC₁₋₁₀alkyl, aryl and heteroaryl, all of which are optionallysubstituted, and one or more of the carbons in C₁₋₁₀alkyl is optionallyreplaced with a heteromoiety selected from O, S, N, NR⁷ and NR⁷R⁸, inwhich R⁷ and R⁸ are independently selected from H and C₁₋₆alkyl.
 22. Themethod according to claim 21, wherein R¹ in the compounds of theformulae II and IV is selected from methyl, ethyl, propyl, butyl,pentyl, ethene, styrene, phenyl, benzyl, thiophene and indole, all ofwhich are optionally substituted.
 23. The method according to claim 22,wherein R¹ in the compounds of the formulae II and IV is optionallysubstituted phenyl.
 24. The method according to claim 20, wherein theoptional substituents on R¹ in the compounds of the formulae II and IVare independently selected from one or more of OH, halo, CN, NO₂,C₁₋₆alkyl, halo-substituted C₁₋₆alkyl, C₁₋₆alkoxy, halo-substitutedC₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆alkenyloxy, aryl, aryloxy,aryl(C₁₋₄alkoxy), heteroaryl, heteroaryloxy, heteroaryl(C₁₋₄alkoxy),NH₂, NH(C₁₋₆alkyl), N(C₁₋₆alkyl)(C₁₋₆alkyl), C(O)C₁₋₆alkyl,C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl, SO₂NH₂, SO₂NHC₁₋₆alkyl and SC₁₋₄alkyl. 25.The method according to claim 24, wherein the optional substituents onR¹ in the compounds of the formulae II and IV are independently selectedfrom one to three of OH, F, Cl, Br, CN, NO₂, CF₃, OCF₃, C₁₋₄alkyl,C₁₋₄alkoxy, phenyl, benzyl, benzyloxy and C(O)OC₁₋₄alkyl.
 26. The methodaccording to claim 20, wherein R¹⁰ in the compounds of the formulae IVand V is selected from phenyl, naphthyl, anthraceneyl,1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl,indenyl, furanyl, thienyl, pyrrolo, pyridyl, indolo and benzofuranyl,all of which are optionally substituted.
 27. The method according toclaim 26, wherein R¹⁰ in the compounds of the formulae IV and V isoptionally substituted phenyl.
 28. The method according to claim 20,wherein the optional substituents on R¹⁰ in the compounds of theformulae IV and V are independently selected from one or more of OH,halo, CN, NO₂, C₁₋₆alkyl, halo-substituted C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted C₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆alkenyloxy, aryl, aryloxy,aryl(C₁₋₄alkoxy), heteroaryl, heteroaryloxy, heteroaryl(C₁₋₄alkoxy),NH₂, NH(C₁₋₆alkyl), N(C₁₋₆alkyl)(C₁₋₆alkyl), C(O)C₁₋₆alkyl,C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl, SO₂NH₂, SO₂NHC₁₋₆alkyl and SC₁₋₄alkyl. 29.The method according to claim 28, wherein the optional substituents onR¹⁰ in the compounds of the formulae IV and V are independently selectedfrom one to three of OH, F, Cl, Br, CN, NO₂, CF₃, OCF₃, C₁₋₄alkyl,C₁₋₄alkoxy, phenyl, benzyl, benzyloxy, naphthyl and C(O)OC₁₋₄alkyl. 30.The method according to claim 20, wherein the method is performed in thepresence of ammonia.
 31. The method according to claim 20, wherein themethod is performed in the presence of an ammonia equivalent of theformula NH₄ ⁺X⁻, in which X is selected from halo, R⁹COO, R⁹SO₄ and BF₄and in which R⁹ is selected from C₁₋₁₀alkyl, C₃₋₂₀cycloalkyl, aryl andheteroaryl, all of which are optionally substituted.
 32. The methodaccording to claim 31, wherein X is Cl or Br.
 33. The method accordingto claim 31, wherein the optional substituents on R⁹ are independentlyselected from one or more of OH, halo, CN, NO₂, phenyl, benzyl,C₁₋₆alkoxy, halo-substituted alkoxy, C₁₋₆alkyl, halo-substituted alkyl,C₂₋₆alkenyl, C₂₋₆alkenyloxy, NH₂, NH(C₁₋₆alkyl),N(C₁₋₆alkyl)(C₁₋₆alkyl), C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl,SO₂NH₂, SO₂NHC₁₋₆alkyl and SC₁₋₄alkyl.
 34. The method according to claim20, wherein the method is performed in a solvent.
 35. The methodaccording to claim 34, wherein the solvent is selected from selectedfrom methanol, ethanol, propanol, butanol, toluene, tetrahydrofuran,acetonitrile, benzene, dioxane, methylene chloride, liquid ammonia,ionic liquids and mixtures thereof.
 36. The method according to claim35, wherein the solvent is dioxane and water.
 37. The method accordingto claim 20, wherein the method is performed at a temperature of from−40° C. to +150° C.
 38. The method according to claim 37, wherein themethod is performed at a temperature of from +50° C. to +120° C.
 39. Themethod according to claim 1 or 20, wherein the method is performed inthe presence of a catalyst.
 40. The method according to claim 39,wherein the catalyst is a transition metal catalyst.
 41. The methodaccording to claim 40, wherein the metal is selected from rhodium,ruthenium, iridium, copper, platinum, palladium and nickel.
 42. Themethod according to claim 41, wherein the metal is rhodium.
 43. Themethod according to claim 39, wherein the catalyst comprises a chiral orachiral ligand.
 44. The method according to claim 43, wherein the chiralligand is a phosphine, diphosphine, aminophosphine, amine, carbene oroxazoline.
 45. The method according to claim 43 wherein in the compoundsof formulae III, R² and R³ are different and enantiomerically enrichedcompounds of formulae Ia and/or Ib are prepared, and in the compounds offormula V, R¹ and R¹⁰ are different and enantiomerically enrichedcompounds of formula IV are prepared.
 46. The method according to claim1 or 20 wherein when R² and R³ are different in compounds of theformulae Ia and/or Ib, and when R¹ and R¹⁰ are different in compounds offormula V, the method further comprises chirally resolving the compoundsof formulae Ia and/or Ib or formula V.
 47. The method according to claim46, wherein the chiral resolution comprises diastereomeric esterformation or diastereomeric salt formation.
 48. The method according toclaim 47, wherein the method further comprises separating thediastereomers using crystallization or chromatography.